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PDBsum entry 4zwz
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Lyase/lyase inhibitor
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PDB id
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4zwz
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References listed in PDB file
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Key reference
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Title
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Mapping selective inhibition of the cancer-Related carbonic anhydrase IX using structure-Activity relationships of glucosyl-Based sulfamates.
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Authors
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B.P.Mahon,
C.L.Lomelino,
J.Ladwig,
G.M.Rankin,
J.M.Driscoll,
A.L.Salguero,
M.A.Pinard,
D.Vullo,
C.T.Supuran,
S.A.Poulsen,
R.Mckenna.
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Ref.
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J Med Chem, 2015,
58,
6630-6638.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be
therapeutically advantageous for treating many types of highly aggressive
cancers. However, designing selective inhibitors for hCA IX has been difficult
due to its high structural homology and sequence similarity with off-target
hCAs. Recently, the use of glucosyl sulfamate inhibitors has shown promise as
selective inhibitors for hCA IX. In this study, we present five X-ray crystal
structures, determined to a resolution of 1.7 Å or better, of both hCA II (a
ubiquitous CA) and an engineered hCA IX-mimic in complex with selected glucosyl
sulfamates and structurally rationalize mechanisms for hCA IX selectivity.
Results from this study have allowed us, for the first time, to empirically
"map" key interactions of the hCA IX active site in order to establish
parameters needed to design novel hCA IX selective inhibitors.
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